This invention relates to novel structural analogs of prostaglandin E compounds which are pharmacological analogs of prostacyclin (PGI.sub.2). In particular, the present invention relates to prostaglandin E-type compounds wherein the C-6 carbon atom is substituted by hydroxy.
Prostacyclin is an endogenously produced compound in mammalian species, being structurally and biosynthetically related to the prostaglandins (PG's). In particular, prostacyclin exhibits the following structural and atom numbering: ##STR1##
As is apparent from inspection of formula I, prostacyclin bears a structural relationship to other endogenously-produced fatty acids, e.g., PGF.sub.2 .alpha. and PGE.sub.2, which respectively exhibit the following structure and atom numbering: ##STR2##
As is apparent by reference to formulas II and III, prostacyclin may be trivially named as a derivative of PGF-type compounds. Accordingly, prostacyclin is trivially named 9-deoxy-6,9.alpha.-epoxy-(5Z)-5,6-didehydro-PGF.sub.1. For description of the geometric stereoisomerism employed above, see Blackwood et al., Journal of the American Chemical Society 90, 509 (1968). Further, for a description of prostacyclin and its structural identification, see Johnson et al, Prostaglandins 12, 915 (1976).
For convenience, both prostaglandin and prostacyclin analogs described herein will be referred to by the trivial, art-recognized system of nomenclature described by N. A. Nelson, Journal of Medicinal Chemistry, 17, 911 (1974) for the prostaglandins. Accordingly, all of the novel prostaglandin analogs will be named as derivatives of PGE.sub.1 or PGE.sub.2.
In formulas I, II, and III above, as well as in formulas hereinafter, broken line attachments to any ring indicate substituents in "alpha" (.alpha.) configuration, i.e., below the plane of such ring. Heavy solid line attachments to any ring indicate substituents in "beta" (.beta.) configuration, i.e., above the plane of such ring. The use of wavy lines (.about.) herein will represent attachment of substituents in either the alpha or beta configuration or attachment in a mixture of alpha and beta configurations.
The side-chain hydroxy at C-15 in the above formulas is in S or R configuration, as determined by the CahnIngold-Prelog sequence rules. See J. Chem. Ed. 41:16 (1964). See also Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins, which discussion applies to the novel prostaglandin analogs herein. Expressions such as C-6, C-15, and the like, refer to the carbon atom in the novel prostaglandin analog which is in the position corresponding to the position of the same number in PGF.sub.2 .alpha., PGE.sub.2, or prostacyclin, as enumerated above.
Molecules of PGF.sub.2 .alpha. and PGE.sub.2 as well as prostaglandin analogs each have several centers of asymmetry, and can exist in racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e., the dextrorotatory and levorotatory forms. As drawn, the above formulas for PGF.sub.2 .alpha., PGE.sub.2, and prostacyclin correspond to that endogenously produced in mammalian tissues. In particular, refer to the stereoconfiguration at C-8 (alpha), C-9 (alpha), C-11 (alpha), and C-12 (beta) of endogenously-produced PGF.sub.2 .alpha. and PGE.sub.2. The mirror image of the above formulas for these prostaglandins represents the other enantiomer. The racemic forms of these prostaglandins contain equal numbers of both enantiomeric molecules, and one of the above formulas and its mirror image is needed to represent correctly the corresponding racemic prostaglandin.
For convenience hereinafter, use of the term prostaglandin ("PG") or prostacyclin ("PGI.sub.2 ") will mean the optically active form of that prostaglandin or prostacyclin thereby referred to with the same absolute configuration as PGF.sub.2 .alpha., PGE.sub.2, or prostacyclin obtained from mammalian tissues.
The term "prostaglandin-type" (PG-type) product, as used herein, refers to any monocyclic or bicyclic cyclopentane derivative herein which is useful for at least one of the same pharmacological purposes as the prostaglandins or prostacyclin.
The formulas as drawn herein, which depict a prostaglandin-type or prostacyclin-type product or an intermediate useful in their respective preparations, each represent the particular stereoisomer of the prostaglandin-type or prostacyclin-type product which is of the same relative stereochemical configuration as a corresponding prostaglandin or prostacyclin obtained from mammalian tissues, or the particular stereoisomer of the intermediate which is useful in preparing the above stereoisomer of the prostaglandin-type or prostacyclin-type products.
The term "prostaglandin analog", as used herein, represents that stereoisomer of a prostaglandin-type product which is of the same relative stereochemical configuration as a prostaglandin obtained from mammalian tissues or a mixture comprising that stereoisomer and the enantiomer thereof. In particular, where a formula is used to depict a prostaglandin-type product herein, the term "prostaglandin analog" refers to the compound of that formula or a mixture comprising that compound and the enantiomer thereof.
The use of 6-hydroxyprostanol derivatives in the preparation of 4,4,5,5-tetradehydro-PG-type compounds is described in U.S. Pat. No. 4,013,695. See especially Chart C therein at columns 27-30 and the text related thereto.